A nerve injury–specific long noncoding RNA promotes neuropathic pain by increasing Ccl2 expression
Shibin Du, Shaogen Wu, Xiaozhou Feng, Bing Wang, Shangzhou Xia, Lingli Liang, Li Zhang, Gokulapriya Govindarajalu, Alexander Bunk, Feni Kadakia, Qingxiang Mao, Xinying Guo, Hui Zhao, Tolga Berkman, Tong Liu, Hong Li, Jordan Stillman, Alex Bekker, Steve Davidson, Yuan-Xiang Tao
Shibin Du, Shaogen Wu, Xiaozhou Feng, Bing Wang, Shangzhou Xia, Lingli Liang, Li Zhang, Gokulapriya Govindarajalu, Alexander Bunk, Feni Kadakia, Qingxiang Mao, Xinying Guo, Hui Zhao, Tolga Berkman, Tong Liu, Hong Li, Jordan Stillman, Alex Bekker, Steve Davidson, Yuan-Xiang Tao
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Research Article Cell biology Neuroscience

A nerve injury–specific long noncoding RNA promotes neuropathic pain by increasing Ccl2 expression

Abstract

Maladaptive changes of nerve injury–associated genes in dorsal root ganglia (DRGs) are critical for neuropathic pain genesis. Emerging evidence supports the role of long noncoding RNAs (lncRNAs) in regulating gene transcription. Here we identified a conserved lncRNA, named nerve injury–specific lncRNA (NIS-lncRNA) for its upregulation in injured DRGs exclusively in response to nerve injury. This upregulation was triggered by nerve injury–induced increase in DRG ELF1, a transcription factor that bound to the NIS-lncRNA promoter. Blocking this upregulation attenuated nerve injury–induced CCL2 increase in injured DRGs and nociceptive hypersensitivity during the development and maintenance periods of neuropathic pain. Mimicking NIS-lncRNA upregulation elevated CCL2 expression, increased CCL2-mediated excitability in DRG neurons, and produced neuropathic pain symptoms. Mechanistically, NIS-lncRNA recruited more binding of the RNA-interacting protein FUS to the Ccl2 promoter and augmented Ccl2 transcription in injured DRGs. Thus, NIS-lncRNA participates in neuropathic pain likely by promoting FUS-triggered DRG Ccl2 expression and may be a potential target in neuropathic pain management.

Authors

Shibin Du, Shaogen Wu, Xiaozhou Feng, Bing Wang, Shangzhou Xia, Lingli Liang, Li Zhang, Gokulapriya Govindarajalu, Alexander Bunk, Feni Kadakia, Qingxiang Mao, Xinying Guo, Hui Zhao, Tolga Berkman, Tong Liu, Hong Li, Jordan Stillman, Alex Bekker, Steve Davidson, Yuan-Xiang Tao

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Figure 4

ELF1 triggers NIS-lncRNA upregulation in injured DRGs following SNL.

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ELF1 triggers NIS-lncRNA upregulation in injured DRGs following SNL. Dat...
Data: mean ± SEM. (A) NIS-lncRNA gene promoter fragment immunoprecipitated by rabbit anti-ELF1 antibody in the ipsilateral L4 DRG 7 days after surgery. n = 36 mice per group. **P < 0.01, by 2-tailed, unpaired Student’s t test. (B and C) Levels of Elf1 mRNA and ELF1 protein in the ipsilateral L4 DRG after surgery. n = 20 mice per time point per group. *P < 0.05, **P < 0.01, by 2-way ANOVA with post hoc Tukey’s test. (D and E) Levels of Elf1 mRNA, NIS-lncRNA), and ELF1 protein in cultured DRG neurons with transfection as indicated. Elf1: AAV5-Elf1; Gfp: AAV5-Gfp; Scr: scrambled shRNA. n = 5 repeats per treatment. **P < 0.01, by 1-way ANOVA with post hoc Tukey’s test. (F) NIS-lncRNA promoter activities in CAD cells transfected as shown. Con: control vector; Elf1: vector expressing Elf1; Gfp, vector expressing Gfp; NIS: pGL3 reporter vector with NIS-lncRNA promoter. n = 5 repeats per treatment. **P < 0.01, by 1-way ANOVA with post hoc Tukey’s test. (G and H) Levels of Elf1 mRNA, NIS V1, and NIS V2 and ELF1 protein in the ipsilateral L4 DRG 5 days after surgery in mice with microinjection of scrambled siRNA (Scr) or Elf1 siRNA 3 days before surgery. n = 20 mice per group. **P < 0.01, by 2-way ANOVA with post hoc Tukey’s test. (I and J) Levels of Elf1 mRNA, NIS V1 and V2, and ELF1 protein in the ipsilateral L3/4 DRGs 7 days after DRG microinjection of NIS-lncRNA siRNA (NIS siRNA) or scrambled siRNA (Scr) in mice with microinjection of AAV5-Gfp (Gfp) or AAV5-Elf1 (Elf1) 35 days before siRNA microinjection. n = 10 mice per group. *P < 0.05, **P < 0.01, by 1-way ANOVA with post hoc Tukey’s test.